"Periodontal disease", as used herein, is a broad term used to describe those diseases which attack the gingiva and the underlying alveolar bone supporting the teeth. Periodontal disease includes a series of diseases exhibiting various syndromes which vary from each other according to the stage or situation of the disease or the age of the patient, and have not been definitely subclassified. The term is used for any inflammatory disease which initially occurs at a marginal gingiva area and may affect the alveolar bone. Two common periodontal diseases are gingivitis (inflammation of the gingiva) and periodontitis (manifested by progressive resorption of alveolar bone, increasing mobility of the teeth, and loss of the teeth at advanced stage). Other terms used for various aspects of periodontal disease include "juvenile periodontitis", "acute necrotizing ulcertive gingivitis", and "alveolar pyorrhea". Periodontal disease is characterized by one or more of the following: inflammation of the gingiva, formation of periodontal pockets, bleeding and/or pus discharge from the periodontal pockets, resorption of alveolar bone, loose teeth and loss of teeth.
Periodontal disease is generally considered to be caused by/associated with bacteria which are generally present in dental plaque which forms on the surface of the teeth and in the periodontal pocket. Known methods for treating periodontal disease often include the use of antimicrobials.
Alveolar bone resorption is a loss of osseous tissue from the specialized bony structure which supports the teeth. Such resorption has many causes including, but not limited to, natural remodeling following tooth extraction, osseous surgery, periodontal flap surgery, dental implants, scaling and root planing and the progression of periodontal disease.
Certain nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be useful in the treatment of periodontal disease, as disclosed in the following references: European Patent Application No. 0,137,668 of the Upjohn Company, inventor Wechter, published April 17, 1985; Waite, I. M., C. A. Saxton, A. Young, B. J. Wagg & M. Corbett, "The Periodontal Status of Subjects Receiving Non-Steroidal Anti-Inflammatory Drugs", Journal of Periodontal Research, Vol. 16 (1981), pp. 100-108; Feldman, R. S., B. Szeto, H. J. Chauncey & P. Goldhaber, "Non-Steroidal Anti-Inflammatory Drugs in the Reduction of Human Alveolar Bone Loss", Journal of Clinical Periodontology, Vol. 10, No. 2 (1983), pp. 131-136; Vogel, R. I., S. A. Copper, L. G. Schneider & D. Goteiner, "The Effects of Topical Steroidal and Systemic Nonsteroidal Anti-Inflammatory Drugs on Experimental Gingivitis in Man", Journal of Periodontology, Vol. 55, No. 4 (1984), pp. 247-251; Vogel, R. I., "The Experimental Use of Anti-Inflammatory Drugs in the Treatment of Periodontal Disease:, Journal of Periodontology, Vol 56 (suppl) (1985), pp. 88-92; Vogel, R.I., L. Schneider & D. Goteiner, "The Effects of a Topically-Active Non-Steroidal Anti-Inflammatory Drug on Ligature-Induced Periodontal Disease in the Squirrel Monkey", Journal of Clinical Periodontology, Vol. 13 (1986), pp. 139-144; Williams, R. C., "Non-Steroidal Anti-Inflammatory Drugs in Periodontal Disease", Non-Steroidal Anti-Inflammatory Drugs, A. J. Lewis, D. E. Furst, eds., Marcel Dekker, pub., (1987), pp. 143-155; Williams, R. C., M. K. Jeffcoat, T. H. Howell, C. M. Hall, H. G. Johnson, W. J. Wechter & P. Goldhaber, "Indomethacin or Flurbiprofen Treatment of Periodontitis in Beagles: Comparison of Effect on Bone Loss", Journal of Periodontal Research, Vol. 22 (1987), pp. 403-407; Rieger, M. M., "Topical Antiinflammatory Therapy Against Periodontal Disease: A Historical Survey", Clinical Preventive Dentistry, Vol. 9, No. 4 (1987), pp. 18-22; Williams, R. C., M. K. Jeffcoat, T. H. Howell, M. S. Reddy, H. G. Johnson, C. M. Hall & P. Goldhaber, "Topical Flurbiprofen Treatment of Periodontitis in Beagles", Journal of Periodontal Research, Vol. 23 (1988), pp. 166-169; Jeffcoat, M. K., R. C. Williams, M. S. Reddy, R. English & P. Goldhaber, "Flurbiprofen Treatment of Human Periodontitis: Effect on Alveolar Bone Height and Metabolism", Journal of Periodontal Research, Vol. 23 (1988), pp. 381-385; Williams, R. C., M. K. Jeffcoat, T. H. Howell, M. S. Reddy, H. G. Johnson, C. M. Hall & P. Goldhaber, "Ibuprofen: An Inhibitor of Alveolar Bone Loss in Beagles", Journal of Periodontal Research, Vol. 23 (1988), pp. 225-229; Heasman, P. A., R. A. Seymour & P. F. Boston, "The Effect of a Topical Non-Steroidal Anti-Inflammatory Drug on the Development of Experimental Gingivitis in Man", Journal of Clinical Periodontology, Vol. 16 (1989), pp. 353-358; Williams, R., M. Jeffcoat, H. Howell, M. Reddy, C. Hall, H. Johnson & P. Goldhaber, "Naproxen Treatment of Periodontitis in Beagles", Journal of Dental Research, (1989), p. 243 (Abstract No. 491 ); Gaffar, A., J. Afflitto, E. J. Coleman, L. Steinberg & D. Fine, "Efficacy of Ibuprofen Rinse in a Subgingival Irrigator on Periodontitis in Primates" , Journal of Dental Research, Vol. 68 (Special Issue) (1989), Abstract No. 830; and Williams, R. C., M. K. Jeffcoat, T. H. Howell, A. Rolla, D. Stubbs, K. W. Teoh, M. S. Reddy & P. Goldhaber, "Altering the Progression of Human Alveolar Bone Loss with the Non-Steroidal Anti-Inflammatory Drug Flurbiprofen, Journal of Periodontology, Vol. 60 (1989), pp. 485-490.
Ketorolac and its pharmaceutically-acceptable, non-toxic esters and salts are known NSAIDs. Ketorolac and its esters and salts, particularly its tromethamine salt, are disclosed in the following references: U.S. Pat. No. 4,089,969 issued to Muchowski & Kluge on May 16, 1978; Rooks, W. H., P. J. Maloney, L. D. Shott, M. E. Schuler, H. Sevelius, A. N. Strosberg, L. Tanenbaum, A. J. Tomolonis, M. B. Wallich, D. Waterbury & J. P. Yee, "The Analgesic and Anti-Inflammatory Profile of Ketorolac and its Tromethamine Salt", Drugs Experimental Clinical Research, Vol. XI, No. 8 (1985), pp. 479-492; and Mroszcsak, E. J., F. W. Lee, D. Combs, F. H. Sarnquist, B-L Huang, A. T. Wu, L. G. Tokes, M. L. Maddox & D. K. Cho, "Ketorolac Tromethamine Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics in Animals and Humans", Drug Metabolism and Disposition, Vol. 15, No. 5 (1987), pp. 618-626.
Several NSAIDs (e.g., ibuprofen and naproxen) are known to have more than one enantiomeric form which differ in properties from one another. Advantages of certain enantiomeric forms of NSAIDs are disclosed in the following references: PCT Patent Application No. W0/00421 of Sunshine & Laska, published January 26, 1989; Caldwell, J., A. J. Hutt & S. Fournel-Gigleux, "The Metabolic Chiral Inversion and Disposition Enantioselectivity of the 2-Arylpropionic Acids and Their Biological Consequences", Biochemical Pharmacology, Vol. 37 (1988), pp. 105-114; and Hutt, A.J. & J. Caldwell, "The Metabolic Chiral Inversion of 2-Arylpropionic Acids--A Novel Route with Pharmacologic Consequences", Journal of Pharmacy and Pharmacology, Vol. 35 (1983), pp. 693-704.
It is an object of the present invention to provide a topical, oral treatment for periodontal disease using ketorolac.
It is also an object of the subject invention to provide a topical, oral treatment for alveolar bone resorption using ketorolac.
It is a further object of the present invention to provide such treatments which result in minimal systemic (blood) concentration of ketorolac.